SUMMARY In the US, there are more than four sports-related traumatic brain injuries every minute. Sports-related concussion (SRC) in youth has received heightened attention due to emerging evidence that SRCs can affect academics, behavior, and neurocognitive processes, such as working memory, concentration, processing speed, and eye and motor function. A recent Institute of Medicine report on SRCs in youth revealed how little is known about concussion in the young brain, and called for urgent attention to determine the incidence of SRCs in boys and girls by sport and demographic; research to identify unbiased, sensitive prognostic and diagnostic metrics/markers; longitudinal studies to determine outcomes; and to delineate age- and sex-related biomechanical determinants of injury risk. This innovative hypothesis-driven Bioengineering Research Grant will generate objective diagnostic tools for use in concussion (Aim 1), new technologies to translate human outcome metrics to animals to provide a human-like platform to develop and test injury treatments in the future (Aim 2), and new knowledge regarding high-risk sports settings for youth (Aim 3) that will drive safety equipment design. The most innovative feature of the study is the integration across Aims to use BOTH male and female high school students and piglets in a deliberately parallel study design to determine optimal SRC assessments and identify mechanistic relationships between sex, loading conditions, and SRC symptoms. The integration of human and animal studies which employ similar neuro-functional assessments leverages the strengths of each approach: human studies ensure the study of biofidelic physiologic processes, and animal studies allow application of specific loading conditions and outcomes not easily measured in living humans, such as neuropathology. Extensive pilot data establish feasibility and sample sizes in all Aims. In Aim 1 an unbiased numerical assessment suite for SRC will be developed and independently validated to establish ?95% sensitivity, and determine if these metrics are predictive of days-to-clearance for sports. Because the Aim 1 objective metrics are nonverbal and effort-independent, they have been ?translated? to animals and reveal human-like physical, cognitive, and sleep symptoms of SRC in animals after rapid controlled head rotations. In Aim 2, single head rotations and multiple sub-concussive rotations are computationally scaled from teens to an immature large animal model of mild TBI, to identify the effects of sex and load frequency, magnitude and direction on neuro-function, biomarkers and neuropathology. Aim 2 will identify biomechanical settings of greatest risk for the young brain. The biomechanical insights from pigs in Aim 2 are translated to teens in Aim 3, where head impact sensors are used to quantify biomechanical load exposure by sport and sex, and the relationships between load exposure and neuro-functional metrics. The proposed studies in animals and humans will have broad impact ? by reducing the healthcare burden of SRC, enhancing accurate and objective diagnosis, and identifying gender-specific prevention and intervention strategies.